General procedure for the synthesis of ethyl (diethoxymethyl)phosphonate from triethyl orthoformate:
1. Synthesis of ethyl (diethoxymethyl)hypophosphite from methanesulfonic acid: under nitrogen protection, triethyl orthoformate (42.1 mL, 253 mmol, 2.1 eq.) was slowly added to a mixture of finely ground ammonium hypophosphite (10 g, 120 mmol, 1.0 eq.), toluene (50 mL), and ethanol (3.5 mL) that had been cooled to 0 °C. The slurry was inerted and maintained at a temperature of about 0 °C. The mixture was then purified by a liquid bath. The slurry was inerted and the temperature was maintained at about 0°C. Methane sulfonic acid (8.4 mL, 127 mmol, 1.05 eq.) was added dropwise over 4 minutes, taking care to control the reaction temperature below 10°C. After the slurry was stirred at 0 °C for 1 h, GC analysis showed 93% conversion of ethyl ester to the target product. After 2 hours of reaction, the reaction was quenched with saturated aqueous sodium bicarbonate (37 mL). The organic phase was separated and concentrated under reduced pressure to 40 °C to give a colorless liquid containing about 50% toluene (28.0 g, GC purity 95%, assayed content 51.2%). Ethyl (diethoxymethyl)hypophosphite was obtained (14.3 g, 73.1 mmol, 61% yield).
2. Scale-up to 2-L scale: Triethyl orthoformate (632 mL, 3.80 mol, 2.1 eq.) was added to a mixture of ammonium hypophosphite (150 g, 1.81 mol, 1.0 eq.), toluene (750 mL), and ethanol (75 mL) cooled to 0 °C under nitrogen protection. The slurry was inerted and the temperature was maintained at about 0°C. Methane sulfonic acid (126 mL, 1.90 mol, 1.05 eq.) was added dropwise over 8 minutes, controlling the temperature below 10°C. After the slurry was stirred at 0 °C for 1 h, GC analysis showed 90% conversion. After 1.5 hours of reaction, the reaction was quenched with saturated aqueous sodium bicarbonate (600 mL). The organic phase was separated and concentrated under reduced pressure to 40°C to give a colorless liquid containing about 65% toluene (579 g, 88% GC purity, 34.4% assay). Ethyl (diethoxymethyl)hypophosphite was obtained (199.2 g, 1.02 mol, 56% yield).
3. Scale-up to 500-L scale: Under nitrogen protection, triethyl orthoformate (133.6 kg, 901.4 mol, 2.1 eq.) was added to a mixture of ammonium hypophosphite (35.6 kg, 429.2 mol, 1.0 eq.), toluene (107 L), and ethanol (11 L) that had been cooled to 0 °C and vigorously stirred. The slurry was inerted and cooled to -0 °C while continuously purged with nitrogen to reduce oxidation by-products. Methane sulfonic acid (43.3 kg, 450.7 mol, 1.05 eq.) was added dropwise over 30 min, controlling the temperature below 10 °C. The slurry was stirred at 0 °C for 2.5 h. After stirring, the reaction was quenched with a mixture of sodium bicarbonate (14.4 kg, 171.7 mol, 0.4 eq.) and water (128 L) to control the temperature below 10 °C. The charge vessel was rinsed with 14 L of water and the reaction mixture was stirred vigorously for 10 minutes. The organic phase was separated and concentrated under reduced pressure to 1/3 of the original volume (82 L, density 0.991 kg/L, 81.3 kg, GC purity 89.6%, assay 61%). Ethyl (diethoxymethyl)hypophosphite was obtained (49.6 kg, 252.7 mol, 58.9% yield).
